A possible target for new epilepsy treatments

Background information
The major role of neurons is to carry messages between different parts of the body. These are transmitted in an electrical form, and they must often travel along several consecutive neurons to reach their destination. Neighbouring neurons communicate with each other through structures known as synapses, which have very narrow gaps. Special chemicals known as a neurotransmitters are needed to carry signals across these spaces.

Neurotransmitters are either excitatory, meaning that the next neuron will fire an electrical signal; or inhibitory, meaning that the next neuron will remain silent. The major excitatory neurotransmitter in the brain is known as glutamate, and the major inhibitory neurotransmitter is called GABA. A fine balance between the two must exist in order for normal brain function to occur. An excess of glutamate can cause neurons to become hyperexcitable and susceptible to seizures.

Neurotransmitters are stored near synapses in small bubbles known as vesicles, which release their contents at the appropriate time. Once emptied, vesicles are recycled (via a process known as endocytosis) so that the reserves of neurotransmitter are maintained. There are several mechanisms through which endocytosis takes place, but during intense neuronal activity (when recycling has to be performed rapidly) it occurs via a process called activity-dependent bulk endocytosis.

The current study
Brain derived neurotrophic factor (BDNF) is a protein that plays a vital role in the growth, development and survival of neurons. Studies have shown that BDNF levels increase in the brain during an epileptic seizure; however until now its role has not been understood. A team of researchers at the University of Edinburgh has recently studied the effect of BDNF on neuronal communication during intense electrical activity (as in a seizure), and they have made some interesting findings.

The group discovered that in conditions of high electrical activity, BDNF blocked activity-dependent bulk endocytosis via a specific signalling pathway. They also found that inhibition of activity-dependent bulk endocytosis led to increased glutamate release at synapses and heightened neuronal excitability.

Implications of the findings
These findings are important because they suggest that inhibition of activity-dependent bulk endocytosis plays a role in epileptic seizures. In theory, therefore, drugs designed to target activity-dependent bulk endocytosis (and override this specific effect of BDNF) should help to decrease excitability and reduce seizure activity. As activity-dependent bulk endocytosis is only triggered during high brain activity, such drugs would potentially have fewer side effects than existing ones. Also, with their completely new mode of action, these drugs would potentially be effective in people who don’t respond to current anti-epileptic drugs.

The researchers emphasise that because activity-dependent bulk endocytosis is also involved in a range of other brain functions, such as creating new memories, a lot more research is needed to establish what the effects of manipulating this process might be (and so the development of new drugs that target it is still a way off). The team is now focusing on the genes that control activity-dependent bulk endocytosis, to see if they hold the key to the design of new treatments.

Professor Mike Cousin, who led the study, said: “Around one third of people with epilepsy do not respond to the treatments we currently have available. By studying the way brain cells behave during seizures, we have been able to uncover an exciting new research avenue for research into anti-epileptic therapies.”

This work builds upon Professor Cousin’s Epilepsy Research UK grant, entitled Mechanism of synaptic vesicle recycling in epilepsy, which he held between 2005 and 2008.

Epilepsy Research UK supports and promotes basic and clinical scientific research into the causes, treatments and prevention of epilepsy; and is the only national charity in the UK that funds independent research exclusively into this condition.

Epilepsy Research UK is a member of the Association of Medical Research Charities